PROJECT SUMMARY/ABSTRACT Despite numerous early life adversities, some children born extremely preterm (< 28 weeks? gestation) remain free of adverse outcomes and have good quality of life. The biological mechanisms underlying protective pathways leading to positive health outcomes among extremely preterm children are not well-understood. However, we do know that placental biology plays a key role in determining child health. In this study, we will integrate multi-omics placental data, including gene expression, epigenetic regulators of gene expression (DNA methylation; microRNAs) and genotype to identify critical pathways linked to positive outcomes among children born extremely preterm. We will investigate an under-studied mechanism?functional changes in gene expression and placental multi-omics?as an early driver of positive health in children. This is the first study to explore placental multi-omics related to positive health. This proposal builds on our preliminary findings from the multi-center Extremely Low Gestational Age Newborns (ELGAN; n = 889) study, from which, (1) we published findings that 32% of ELGAN children exhibited no adverse health outcomes at age 10, and derived a positive child health index, strongly associated with quality of life scores; (2) we identified protective prenatal factors (e.g., higher maternal education) associated with positive child health that potentially effect biological pathways influencing health outcomes; and (3) we found that children with positive health at age 10 had reduced expression of inflammatory genes in the placenta compared with children with adverse outcomes (preliminary data). The central hypothesis of this proposed study is that reduced placental gene expression of inflammatory and stress-related pathways is associated with positive child health. We anticipate that these functional changes in gene expression are tied to microRNAs (miRNAs), DNA methylation and genotype. Our specific aims are to: 1) identify placental gene expression (mRNAs) changes associated with protective prenatal factors and positive child health outcomes at ages 10 and 15 years; and 2) determine regulators (e.g., DNA methylation) of gene expression associated with protective prenatal factors and positive child health at ages 10 and 15. This proposal builds on the existing data of the ELGAN study, which enrolled a cohort of children born < 28 weeks? gestation, with follow-up rates of > 80%. From the ELGAN study (funded in the NIH Environmental influences on Child Health Outcomes (ECHO) program), we have access to: a) placental multi-omics data: gene expression (mRNAs), epigenetic transcriptional and post-transcriptional regulators of gene expression (miRNAs and DNA methylation, respectively), and gene sequences (genotype); b) child outcome at ages 10 and 15 years, robust measures of positive child health outcomes; c) prenatal and age 2 years factors: measures of prenatal factors and life adversities related to child health to use as covariates. This study is innovative because it will redirect research and public health efforts to identify biological pathways and antecedents of positive health amenable to laboratory testing and clinical trials to advance prediction and prevention of outcomes in at-risk children.